Drugging RNA with pills: small molecules for a big frontier

Editor’s note: BioPharma Dive, as part of its newly launched Emerging Biotech Weekly, is taking a closer look at competitive areas of startup activity. We aim to give an overview of the companies developing a new technology and what their goals are. This, on RNA-targeting small molecules, is our fourth.

Infused or injectable medicines that interfere with RNA, the messenger molecules that turn genetic instructions into proteins, have taken the spotlight in recent years, winning approvals for several rare diseases. A group of biotechnology startups are trying to find similar success by targeting RNA with pills instead.

History shows they face a daunting task. It’s long been considered futile to use chemical-based compounds to go after RNA because of its shifty nature. When scientists have succeeded, it’s typically been by accident. Last decade, for instance, Merck & Co. discovered an experimental antibiotic it was developing blocked a type of bacterial RNA. Pfizer inadvertently found one of its drug prospects affected translation of a protein that regulates cholesterol.

Now, drugmakers are doing it intentionally. Helped by better sequencing technologies, screening methods and a broader understanding of RNA, researchers can more easily capture how the information molecules look and design drugs that attach to them.

If successful, they could help unlock disease targets that small molecules can’t currently reach, bringing forward new ways to treat neurodegenerative disorders, cancer and other diseases.

At least eight startups are developing small molecules that target RNA. Large pharmaceutical companies including Sanofi, AstraZeneca, Amgen and Roche have shown interest in their research, promising hundreds of millions of dollars in a string of deals. Here’s where things stand.

What are RNA-targeting small molecules, and how do they work?

Small molecules are chemical-based drugs that usually target proteins and block or change the way they work.

Due to their size, they can reach most tissues in the human body, slip into cells and bind to the craggy parts of their targets. They are the bedrock of the pharmaceutical industry, making up a large majority of drugs on the market.

But small molecules have limited reach. About 3,000 of the roughly 20,000 known genes are considered “druggable,” meaning they can be targeted by a medicine. Of the proteins they produce, only a few hundred are targeted by available drugs. Many of the others don’t have the well-defined pockets that small molecules can nestle into, making them more challenging to reach.

Targeting the RNA molecules that help make disease-associated proteins could give drugmakers an alternate route. In theory, such a drug could stop production of a potentially harmful protein, or make more of a helpful one.

For example, Arrakis Therapeutics is working on a medicine that would block the body from making a well-known, but long thought “undruggable,” cancer protein called Myc. An experimental Expansion Therapeutics drug destroys RNA implicated in a type of muscular dystrophy. Accent Therapeutics and Storm Therapeutics, meanwhile, aim to target the special proteins involved in transcribing and modifying RNA.

They and others in the field face significant challenges, such as finding the right RNA sequences and, within them, the correct locations to target. They also need to ensure their small molecules only stick to their intended targets and not other RNA, which could lead to side effects or other health risks.

What advantages would RNA-targeting small molecules have over existing technologies?

Drugs that interfere with RNA have proven to be powerfully effective tools to treat a range of diseases.

One method, pioneered by Alnylam Pharmaceuticals and known as RNA interference, involves using small, synthetic RNA molecules to “silence” genes and prevent them from creating harmful proteins. Another, similar method, used by Ionis Pharmaceuticals and others, uses strips of nucleic acid called antisense oligonucleotides to adjust or shut off protein production.

Both have advanced RNA drug research, leading to medicines for rare genetic diseases such as spinal muscular atrophy and transthyretin amyloidosis, as well as more common conditions like high cholesterol. The effects of the medicines can last up to months at a time.

While significant progress has been made in delivering these kinds of RNA therapies into the body, they’re still largely restricted to disease targets in the liver, meaning there are many diseases they can’t yet treat.

Research has also noted their propensity to trigger immune responses and, in some cases, difficulty in crossing the blood-brain barrier or entering cells.

Small molecules could help solve these problems. They’re a better known quantity to drugmakers, easier to deliver than nucleic acid-based therapies and, because they’re taken orally, are more convenient for patients.

Small molecules might also be better at permeating cell walls and are more easily absorbed and taken up by the body. They’re cheaper to manufacture, too.

Which companies are working on small molecules that target RNA?

At least eight startups have formed to develop oral RNA-targeting drugs. Half have already caught the eye of bigger pharmaceutical companies looking to invest in the field.

The most richly funded, Skyhawk Therapeutics, has raised at least $181 million in private funding and equity, and more than $400 million in upfront cash from partnerships, according to the company. In July, Sanofi partnered with Skyhawk to develop drugs for cancer and research programs for oncology and immune diseases. Skyhawk also has deals in place with Merck, Biogen and Vertex Pharmaceuticals.

Arrakis, launched in 2015 by a team of Biogen veterans, has raised $113 million to date. Its research has drawn the attention of first Roche and then Amgen, which handed the company a combined $265 million through deals to develop medicines aimed at a variety of disease targets.

Accent has also been successful in luring big pharma, having signed partnerships with AstraZeneca and Ipsen. The company, which is focusing on cancer research, has also raised more than $100 million in venture funding.

Remix Therapeutics joined the field more recently, launching late in 2020 with $81 million in funding. The company added another $70 million this May, a few months after it teamed up with Johnson & Johnson.

Expansion, formed by pioneering RNA researchers at the Scripps Research Institute, has secured $135 million in funding and is backed by a wide range of investors including the venture arms of Sanofi and Novartis.

Storm, Gotham Therapeutics (which was folded last year into another private biotech called 858 Therapeutics) and Twentyeight-Seven Therapeutics are also researching RNA-targeting small molecules. Storm formed a cancer drug collaboration with Exelixis in 2021.

What is the status of the technology?

While several drugs built on other RNA technologies have made it to market in recent years, small molecules capable of targeting RNA are just beginning to show their potential.

The first to do so was Evrysdi, a drug from Roche and PTC Therapeutics that was approved in 2020 and helps produce a protein that people with spinal muscular atrophy lack. An experimental Huntington’s disease drug from Novartis, known as branaplam, is also in human testing, though recent safety concerns could derail its progress.

So far, none of the startups developing RNA-targeting small molecules have brought a drug prospect into clinical testing. The pipelines for some are beginning to take shape, however.

Skyhawk Therapeutics appears on the cusp of entering clinical trials, previously indicating plans to begin to advance its first drug into human testing sometime this year.

has previously said it expected to test its two lead therapies, both neurodegenerative disease treatments, in humans by the end of 2021. Storm plans to launch a clinical trial for a cancer drug by the end of this year and Accent is working to push forward a cancer medicine with Ipsen. Both candidates target METTL3, an enzyme that affects RNA function.

Arrakis lists early research programs for cancer, dyslipidemia and a COVID-19 antiviral as its most advanced targets. Expansion, meanwhile, is pursuing drugs for muscular dystrophy and ALS.

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